Cognitive Dysfunction and Diabetes Mellitus: Christopher T. Kodl and Elizabeth R. Seaquist

0163-769X/08/$20.
00/0 Endocrine Reviews 29(4):494 –511

Printed in U.S.A. Copyright © 2008 by The Endocrine Society
doi: 10.1210/er.2007-0034
Cognitive Dysfunction and Diabetes Mellitus

Christopher T. Kodl and Elizabeth R. Seaquist
Department of Medicine, Division of Endocrinology and Metabolism, University of Minnesota, Minneapolis, Minnesota
55455
The deleterious effects of diabetes mellitus on the retinal, significant roles. Modalities to study the effect of diabetes on
renal, cardiovascular, and peripheral nervous systems are the brain have evolved over the years, including neurocogni-
widely acknowledged. Less attention has been given to the tive testing, evoked response potentials, and magnetic reso-
effect of diabetes on cognitive function. Both type 1 and type 2 nance imaging. Although much insightful research has exam-
diabetes mellitus have been associated with reduced per- ined cognitive dysfunction in patients with diabetes, more
formance on numerous domains of cognitive function. The needs to be understood about the mechanisms and natural
exact pathophysiology of cognitive dysfunction in diabetes is history of this complication in order to develop strategies for
not completely understood, but it is likely that hyperglycemia, prevention and treatment. (Endocrine Reviews 29: 494 –511,
vascular disease, hypoglycemia, and insulin resistance play 2008)
I. Introduction nitive dysfunction, and many patients fear that recurrent

II. Cognitive Dysfunction in Patients with Diabetes hypoglycemia will impair their memory over time. Although
A. Type 1 diabetes much research has been done, the pathophysiology under-
B. Type 2 diabetes lying this complication is not well understood, and the most
C. Hypoglycemia and cognitive dysfunction appropriate methods to diagnose, treat, and prevent cogni-
D. Section summary tive dysfunction in diabetes have not yet been defined. In this
III. Pathophysiology of Cognitive Dysfunction in Diabetes article, we will review the nature of cognitive dysfunction in
A. The role of hyperglycemia type 1 and type 2 diabetes mellitus, the pathophysiology of
B. The role of vascular disease cognitive dysfunction secondary to diabetes, methodologies
C. The role of hypoglycemia
used to assess cognitive deficits in patients with diabetes, and
D. The role of insulin resistance and amyloid
potential future directions of research that are needed to
IV. Modalities for Assessment of Cognitive Dysfunction in
Patients with Diabetes
advance our understanding of this often overlooked com-
V. Future Directions plication of diabetes.
VI. Conclusion The purpose of this article is to present a comprehensive
review of the literature regarding the subject of cognitive
dysfunction in diabetes mellitus. To do this, we performed
I. Introduction MEDLINE searches for such key words and terms as “diabetes
mellitus,” “cognitive function,” “cognition,” “hypoglycemia,”
D IABETES MELLITUS IS a complex metabolic disease
that can have devastating effects on multiple organs
in the body. Diabetes is the leading cause of end stage renal
“insulin resistance,” and “Alzheimer’s disease,” among others.
We then pursued articles referenced in these sources. Although
this is a comprehensive review, it is not exhaustive. In addition,
disease in the United States (1) and is also a common cause
it should be noted that the field of cognitive dysfunction in
of vision loss, neuropathy, and cardiovascular disease. A less
diabetes is still in its early stages. It must be remembered that
addressed and not as well recognized complication of dia-
although there have been many significant contributions re-
betes is cognitive dysfunction. Patients with type 1 and type
garding the association of diabetes and cognitive dysfunction
2 diabetes mellitus have been found to have cognitive deficits
and many hypotheses based on this association, the causative
that can be attributed to their disease. Both hypoglycemia
mechanisms of diabetes on cognitive dysfunction are still un-
and hyperglycemia have been implicated as causes of cog-
dergoing development.
First Published Online April 24, 2008

Abbreviations: AGE, Advanced glycation end product; APOE-␧4, II. Cognitive Dysfunction in Patients with Diabetes
apolipoprotein E type 4; APP, amyloid precursor protein; DCCT, Dia-
betes Control and Complications Trial; EEG, electroencephalograph(y); A. Type 1 diabetes
fMRI, functional MRI; GLUT, glucose transporter; HbA1c, glycated he-
moglobin; MRI, magnetic resonance imaging; NMDA, N-methyl-d- Cognitive dysfunction in patients with diabetes mellitus
aspartate; PET, positron emission tomography; PPAR-␥, peroxisome
was first noted in 1922, when patients with diabetes, who
proliferator-activated receptor-␥; SPECT, single photon emission com-
puted tomography. were “free from acidosis but usually not sugar free,” were
Endocrine Reviews is published by The Endocrine Society (http:// noted to have impaired memory and attention on cognitive
www.endo-society.org), the foremost professional society serving the testing compared with controls (2). Since then, there have
endocrine community. been many studies designed to better delineate the scope and
494
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Kodl and Seaquist • Cognition and Diabetes Mellitus Endocrine Reviews, June 2008, 29(4):494 –511 495
TABLE 1. Summary of cognitive domains that have been found to tions, but not with glycemic control in these populations.
be negatively affected by type 1 diabetes mellitus However, this last finding was confounded by the hetero-
geneity of how different studies defined “well” vs. “poorly”
Slowing of information processing*
Psychomotor efficiency* controlled diabetes (22).
Attention* As was demonstrated in the work of Brands et al. (22),
Memory cognitive function may be worse in patients with type 1
Learning diabetes who experience other diabetes complications. Def-
Problem solving
Motor speed icits in fluid intelligence, information processing, attention,
Vocabulary and concentration have been associated with the presence of
General intelligence background retinopathy (23). Proliferative retinopathy, ma-
Visuoconstruction* crovascular complications, hypertension, and duration of
Visual perception
diabetes were associated with poorer performance on tests
Somatosensory examination
Motor strength measuring psychomotor speed and visuoconstruction ability
Mental flexibility* in patients with type 1 diabetes (4 – 6). Patients with distal
Executive function symmetrical polyneuropathy displayed worse cognitive
Domains marked by asterisks have particularly strong support- function on most cognitive domains except for memory (5).
ing data. However, other studies were unable to identify a relation-
ship between impaired cognitive function and diabetic com-
magnitude of cognitive dysfunction in diabetes (Table 1). The plications (24). Future study will be necessary to determine
most common cognitive deficits identified in patients with whether there is a link between complications and alterations
type 1 diabetes are slowing of information processing speed in cognition.
(3– 6) and worsening psychomotor efficiency (3, 4, 7). How- Although complications like retinopathy and nephropa-
ever, other deficits have been noted, including deficits in thy usually require years of diabetes before becoming clin-
motor speed (5, 8 –10), vocabulary (7, 11–13), general intel- ically apparent, the onset of cognitive impairment has been
ligence (12, 14), visuoconstruction (6, 12), attention (6), so- found to occur early in patients with type 1 diabetes. Deficits
matosensory examination, motor strength (10), memory (7), in cognitive function have been detected as early as 2 yr after
and executive function (7, 14). Glycemic control appears to diagnosis in children with type 1 diabetes, and these patients
play a role in cognitive performance in patients with type 1 experienced less positive changes than controls over time in
diabetes. Functions such as psychomotor efficiency, motor general intelligence, vocabulary, block design, speed of pro-
speed (5, 15), attention, verbal IQ scores (16 –18), memory, cessing, and learning (12). Six years after diagnosis, these
and academic achievement (17) are improved with better same subjects had impaired IQ, attention, processing speed,
glycemic control. Specifically, an 18-yr follow-up of the Di- long-term memory, and executive function compared with
abetes Control and Complications Trial (DCCT) showed that controls (14). The age of onset of type 1 diabetes may also
those patients with type 1 diabetes mellitus with a time contribute to the presence of cognitive dysfunction, because
weighted mean glycated hemoglobin (HbA1c) less than 7.4% those who developed type 1 diabetes at less than 4 yr of age
performed significantly better on tests of motor speed and had impaired executive skills, attention, and processing
psychomotor efficiency than those subjects whose time speed when compared with those that were diagnosed after
weighted mean HbAlc was greater than 8.8% (15). In addi- 4 yr of age (14). Of note, chronic disease and time away from
tion, slowing of all cognitive function, an increased number school (secondary to illness, etc.) were not controlled for in
of mental subtraction errors (19), loss of inhibition and focus these studies.
(20), impaired speed of information processing, decreased Interestingly, several studies have shown patient gender
attention, and impaired working memory (21) have all been to influence neurocognitive function in patients with type 1
noted during acute hyperglycemia in patients with type 1 diabetes mellitus. Skenazy and Bigler (10) found that men
and type 2 diabetes. with type 1 diabetes had reduced performance on oscillation,
A recent meta-analysis included 33 studies examining cog- strength grip, and somatosensory testing compared with
nitive function in adult subjects with type 1 diabetes mellitus male controls, and the magnitude of this difference was
(22). It found that there were significant reductions in overall greater than that measured between women with type 1
cognition, fluid and crystallized intelligence, speed of infor- diabetes and their gender-matched controls. In addition, a
mation processing, psychomotor efficiency, visual and sus- decline in verbal intelligence was seen in boys with type 1
tained attention, mental flexibility, and visual perception in diabetes between the ages of 7 and 16, which correlated with
subjects with type 1 diabetes compared with controls. There worse glycemic control. This was not seen in girls of similar
was no difference in memory, motor speed, selective atten- ages (13). However, most human studies have not distin-
tion, and language. All studies included healthy matched guished between genders when describing results of neu-
control groups and used reliable testing measures at normal rocognitive testing, and therefore more controlled analysis
blood glucose values. Most studies included in the meta- should be done before any conclusions are drawn.
analysis controlled for depression; however, similar findings Of note, the strength of these neurocognitive studies is
were seen in those studies that did not control for depression. variable. Covariates that could affect neurocognitive testing
It is unclear whether any of these studies controlled for other include age, education, sex, history of other chronic illnesses,
chronic diseases that could affect cognitive function. Worse psychiatric disorders, neurological disorders, substance
cognition was associated with increased diabetes complica- abuse, absence from school, socioeconomic status, and hy-
496 Endocrine Reviews, June 2008, 29(4):494 –511 Kodl and Seaquist • Cognition and Diabetes Mellitus
poglycemia/hyperglycemia during testing. The reviewed reserved (46). In a population of nearly 2000 postmenopausal
ports controlled for at least some of these covariates, however women, Yaffe et al. (47) found that those with a HbA1c of
most fail to control for all of them. For example, only two more than 7.0% had a 4-fold increase in developing mild
studies that have been mentioned (6, 24) have reported con- cognitive impairment. Grodstein et al. (30) found that elderly
trolling for hyperglycemia at the time of testing, which has subjects who took oral diabetic medication, unlike those on
been proven to affect cognitive function (see Section II.A). The insulin, had similar scores on general tests for cognition as
cognitive domains that are affected by type 1 diabetes with subjects without diabetes. Other studies have demonstrated
the best evidence based on our review are indicated in Table 1 an inverse relationship between HbAlc and working mem-
with an asterisk. ory (27, 28), executive functioning (27), learning (26), and
complex psychomotor performance (26, 48) in patients with
B. Type 2 diabetes type 2 diabetes mellitus, supporting the hypothesis that
worsening glucose control leads to worsening cognitive
Patients with type 2 diabetes mellitus have also been function much like with type 1 diabetes. Also similar to type
found to have cognitive impairment (Table 2). Type 2 dia- 1 diabetes is the association between alterations in cognitive
betes has been associated with decreases in psychomotor function in patients with type 2 diabetes and diabetes com-
speed (25, 26), frontal lobe/executive function (26–28), verbal plications like peripheral neuropathy (28) and duration of
memory (29), processing speed (29), complex motor func- type 2 diabetes (25, 33).
tioning (26), working memory (27, 28), immediate recall, Impaired glucose tolerance without diabetes is also a risk
delayed recall (30), verbal fluency (26, 31), visual retention factor for cognitive dysfunction. Multiple investigations of
(32), and attention (33). The impact of these subtle neuro- patients with impaired glucose tolerance have shown them
cognitive deficits on the daily lives of patients with type 2 to have lower mini-mental status exam and long-term
diabetes is not clear. Sinclair et al. (34) found that subjects memory scores (49), impaired verbal fluency (31), increased
with mini-mental status exam scores less than 23 fared worse Alzheimer’s dementia (39), and increased vascular dementia
on measures of self care and ability to perform activities of (38) compared with control subjects. These observations mir-
daily living. These subjects also displayed an increased need ror the positive relationship found between hyperglycemia
for personal care and increased rates of hospitalization when in patients without diabetes and cardiovascular disease
compared with controls. Patients with diabetes also have (50 –52). The pathophysiology of this relationship is unclear,
been found to have slower walking speed, lack of balance, and there is evidence that both hyperglycemia and other
and increased falls associated with type 2 diabetes, but aspects of insulin resistance could contribute to this, which
whether the cerebral affects of diabetes contributed to these will be addressed later. Of note, however, not all studies found
abnormalities is debatable (35). Complicating the impact of that patients with impaired glucose tolerance (33, 53, 54) or type
mild neurocognitive dysfunction secondary to diabetes on 2 diabetes mellitus (54, 55) perform worse than normoglycemic
daily living is the observation that patients with diabetes are individuals.
twice as likely to have depression (27, 36), which will also However, like neurocognitive studies examining type 1
negatively affect cognitive function and daily activities. Type diabetes, the strength of these neurocognitive studies eval-
2 patients also have an increased incidence of Alzheimer’s uating type 2 diabetes and impaired glucose tolerance is
disease (37– 44) and increased incidence of vascular dementia variable. Although most of these studies controlled for
(38, 42, 45). Recently, Bruce et al. (36) found that 17.5% of age, there was uneven control for other covariates includ-
elderly patients with type 2 diabetes had moderate to severe ing education, psychiatric disorders, neurological disorders,
deficits in activities of daily living, 11.3% had cognitive im- hyperglycemia and hypoglycemia during testing, and chronic
pairment, and 14.2% had depression. illness. The cognitive domains that are affected by type 2 dia-
Glycemic control appears to play a role in determining the betes with the best evidence based on our review are indicated
degree of cognitive dysfunction detected in patients with in Table 1 with an asterisk.
type 2 diabetes, although this has not uniformly been ob-
TABLE 2. Summary of cognitive domains that have been found to C. Hypoglycemia and cognitive dysfunction
be negatively affected by type 2 diabetes mellitus
Repetitive episodes of moderate to severe hypoglycemia
Memory* have been implicated as one possible etiology of cognitive
Verbal memory dysfunction in diabetes. This is significant because the risk of
Visual retention hypoglycemia increases as efforts to achieve the level of
Working memory
Immediate recall
glycemia necessary to minimize the risk of developing
Delayed recall the microvascular complications of diabetes are intensified
Psychomotor speed* (56 –58). The reason for severe hypoglycemia secondary to
Executive function* intensive insulin management is complex and multifactorial,
Processing speed however the initial intelligence of patients with type 1 dia-
Complex motor function
Verbal fluency betes before intensive management does not predispose to
Attention more future hypoglycemia episodes, as shown by an analysis
Depression of data collected during the DCCT (59). During acute hypo-
Domains marked by asterisks have particularly strong support- glycemia episodes, it has been shown that performance
ing data. on immediate verbal memory, immediate visual memory,
working memory, delayed memory, visual-motor skills, visual- frequent episodes of hypoglycemia (⬍70 mg/dl) actually
spatial skills, and global cognitive dysfunction are all impaired had increased memory and verbal scores, as well as overall
(60, 61). In a more recent study, prospective memory (that is, better academic achievement when compared with less well-
“remembering to remember”) and immediate and delayed re- controlled children with diabetes.
call were both impaired secondary to hypoglycemia in patients
with type 1 diabetes, suggesting that impairments with both D. Section summary
recall and learning/consolidation occur during hypoglycemia
(62). Interestingly, in some studies there was no difference in Clearly, much research has been done on cognitive dys-
reaction time (63), memory (62), and overall cognitive perfor- function in patients with type 1 and type 2 diabetes mellitus.
mance (61) between hypoglycemia aware and unaware patients Although results are not consistent and many different def-
during hypoglycemic episodes, despite the fact that the glucose icits have been identified, some conclusions can be drawn. In
level at which the counterregulatory hormone response was patients with type 1 diabetes mellitus, deficits in speed of
elicited was higher in subjects with awareness of hypoglycemia. information processing, psychomotor efficiency, attention,
Although cognitive impairment may occur during hypo- mental flexibility, and visual perception seem to be present,
glycemia, the effect of repetitive hypoglycemia on subse- whereas in patients with type 2 diabetes, an increase in
quent cognitive function during euglycemia is less clear. memory deficits, a reduction in psychomotor speed, and
Studies have shown impaired verbal IQ scores (14, 64), full reduced frontal lobe/executive function have been identi-
scale IQ scores (14, 20, 64), attention (20), verbal skills (11), fied. Severe hypoglycemic episodes may contribute to cog-
short-term memory, verbal memory (17), vigilance (65), and nitive dysfunction in the young; however, as patients age
visual-spatial memory (8, 18) in patients with a history of episodes seem to have less of an influence. Finally, improved
type 1 diabetes and severe hypoglycemia (defined as being diabetes control and decreased diabetic complications seem
associated with seizures, coma, or the need for external as- to be associated with less cognitive dysfunction, although
sistance), compared with patients with type 1 diabetes with- this association is clearer in patients with type 2 diabetes than
out a history of severe hypoglycemia. However, it is possible with type 1 diabetes.
that some of these “abnormalities” could be the result of However, some questions remained unanswered. First, it
slower, more deliberate completion of the tasks without loss is not clear whether cognitive impairments seen in neuro-
of accuracy (66). More recently, no association between mul- cognitive testing result in meaningful deficits either socially
tiple severe episodes of hypoglycemia and impaired cogni- or professionally. Given the subjective nature of assessing
tive function in patients with type 1 diabetes mellitus was professional and social activities, it will be difficult to address
found in an 18-yr follow-up of the DCCT (15). Although the this question. Second, although the data suggest that hyper-
DCCT follow-up has been regarded as a landmark study that glycemia contributes to cognitive impairment, the magni-
provides reassurance to diabetologists and patients, it is im- tude of this contribution and how hyperglycemic one must
portant to recognize its limitations, including the fact that it be to experience the ill effects of hyperglycemia on cognition
did not randomize patients into a “severe hypoglycemia” are not clear. Lastly, it is unknown whether mild neurocog-
group and a control group (because such randomization nitive impairments will progress to overt dementia. Large
would be not only logistically impossible but also unethical). randomized controlled trials such as the Epidemiology of
A lack of association between severe hypoglycemia and cog- Diabetes Interventions and Complications (EDIC) study/
nitive dysfunction was confirmed by other studies (23, 68 – DCCT and the ongoing Action to Control Cardiovascular
71), as well as with a meta-analysis, which showed no as- Risk in Diabetes (ACCORD) study should hopefully con-
sociation between hypoglycemia and cognitive function (22). tinue to address these last two questions.
Of note, however, most data analyzing the effects of hypo-
glycemia look at young to middle-aged patients; data re-
III. Pathophysiology of Cognitive Dysfunction in
garding the impact of hypoglycemia on older individuals is
Diabetes
lacking.
One possible reason that some studies found an associa- The pathophysiology underlying the development of cog-
tion between frequent hypoglycemia and cognitive dysfunc- nitive dysfunction in patients with diabetes has not been
tion and others did not is that the positive investigations may completely elucidated. Many hypotheses with supporting
have included subjects with diabetes onset earlier in life. evidence exist, including potential causative roles for hyper-
Patients with type 1 diabetes diagnosed at less than 5 yr of glycemia, vascular disease, hypoglycemia, insulin resistance,
age may have more severe (often with seizures) and frequent and amyloid deposition (Fig. 1). Although further research
hypoglycemia episodes than those diagnosed at ages older into each of these candidate mechanisms is necessary, it may
than 5 yr; these younger patients have been found to have be that the cause of cognitive dysfunction in patients with
worse cognitive dysfunction (9, 18, 72, 73). The severity of the diabetes will turn out to be a combination of these factors,
hypoglycemia as well as the susceptibility of young brains to depending on the patient’s type of diabetes, comorbidities,
injury may explain the discrepancy (9, 74). Another expla- age, and type of therapy.
nation for discrepancy between reports is that subjects with
more hypoglycemia may have overall tighter glycemic con- A. The role of hyperglycemia
trol, which may offset the neurocognitive damage from hy-
poglycemia. This was most likely the case in the population As reviewed in Sections II.A and II.B, hyperglycemia ap-
studied by Kaufman et al. (17) in which children with more pears to be related to abnormalities in cognitive function in
Hyperglycemia-
Induced End Organ
Damage
“Microvascular Disease”
“Macrovascular
Insulin Resistance
Disease”
Cerebrovascular
Accident
Cognitive Dysfunction in
Diabetes Mellitus
Absence of
Hypoglycemia
C-Peptide
Absence of
Apoε 4 Allele
FIG. 1. Summary of possible mechanistic contributors to cognitive dysfunction seen in diabetes mellitus. Not all mechanisms are present in
every patient.
patients with both type 1 and type 2 diabetes. However, the function normally seen in rats with hyperglycemia (80).
mechanisms through which hyperglycemia might mediate Whether this pathway contributes to neurocognitive dys-
this effect are less than clear. In other organs, hyperglycemia function in humans with diabetes is unknown.
alters function through a variety of mechanisms including The role of AGEs and receptors for AGE (RAGEs) in the
polyol pathway activation, increased formation of advanced development of cerebral complications of diabetes also re-
glycation end products (AGEs), diacylglycerol activation of mains uncertain. Diabetic mice (32% HbA1c vs. 12% in con-
protein kinase C, and increased glucose shunting in the hex- trol mice) with demonstrated cognitive impairment have
osamine pathway (75–78). These same mechanisms may be been found to have increased expression of RAGEs in neu-
operative in the brain and induce the changes in cognitive rons and glial cells and damage to white matter and myelin
function that have been detected in patients with diabetes. (78), suggesting a possible role of RAGEs in the development
It has long been known that hyperglycemia increases of cerebral dysfunction (81). In humans, patients with dia-
flux through the polyol pathway in nervous tissue. In the betes and Alzheimer’s disease have been found to have
streptozotocin-treated rat (glucose concentration 27.4 ⫾ 0.3 greater N-carboxymethyllysine (a type of AGE) staining on
mmol/liter vs. 5.9 ⫾ 0.1 mmol/liter in control rats), an in- brain slices obtained postmortem than patients with Alzhei-
crease in sorbitol was measured in cranial nerves, sciatic mer’s disease alone (82). However, a second autopsy study
nerve, cerebral cortex, and retina. This accumulation was failed to find a difference in the quantity of AGE-like glycated
reduced significantly when the animals were treated with the protein rich neurofibrillary tangles and senile plaques, like
aldose reductase inhibitor tolerstat (79). Another study look- those seen in patients with Alzheimer’s disease, between
ing at streptozotocin-treated rats (HbA1c 7.9 ⫾ 0.3 vs. 3.3 ⫾ human subjects with diabetes and controls (83). Experiments
0.0 in control rats) also found that administering an aldose performed in animal models provide limited evidence to
reductase inhibitor, sorbinil, reduced the accumulation of support the hypothesis that AGE-induced brain injury may
brain tissue sorbitol and corrected the reduced cognitive be a mechanism through which hyperglycemia and diabetes
alter cerebral function. In vitro the addition of AGEs to bovine acetylcholine (91), decreased serotonin turnover, decreased
brain microvascular endothelial cells up-regulates both tis- dopamine activity, and increased norepinephrine (86, 92) in
sue factor mRNA (which induces blood coagulation) and the brains of animals with diabetes. Interestingly, these changes
reactive oxygen species through a mechanism that is re- were all reversed with insulin. One proposed hypothesis is that
versed with treatment by the free radical scavenger edara- the alternating high and low glucose levels seen in patients
vone (84). In addition, in a rat model of focal cerebral isch- with poorly controlled diabetes may worsen neurotransmitter
emia, the infusion of AGEs increased cerebral infarct size, function (92).
whereas the coadministration of aminoguanidine, an inhib-
itor of AGE cross-linking, attenuated the infarct volume (85).
Few investigators have examined the role of diacylglycerol B. The role of vascular disease
activation of protein kinase C and increased glucose shunting
in the development of cognitive dysfunction in diabetes. Patients with diabetes have a 2- to 6-fold increased risk in
Brain expression of protein kinase C-␣ was shown to be thrombotic stroke (41, 93), and vascular disease has long been
significantly increased in one untreated diabetic rat model hypothesized to contribute to abnormalities in cognition in
(approximate blood glucose, 15 mmol/liter) compared with such patients. Autopsy studies on patients with long-stand-
the treated diabetic rat and control rats (approximate blood ing type 1 diabetes have shown changes related to vascular
glucose, 6 mmol/liter) (86), but another study found no disease, including diffuse brain degeneration, pseudocalci-
increase in protein kinase C activity in diabetic rats (approx- nosis, demyelination of cranial nerves and spinal cord, and
imate blood glucose, 17 mmol/liter) compared with controls nerve fibrosis (94, 95). Thickening of capillary basement
(approximate blood glucose, 6.4 mmol/liter) (87). Support membranes, the hallmark of diabetic microangiopathy, has
for the possible role of the hexosamine pathway comes from
been found in the brains of patients with diabetes (96). Pa-
the interesting observation that cerebral chitin, an N-acetyl-
tients with diabetes have also been found to have decreased
glucosamine polymer produced via the hexosamine path-
global rates of cerebral blood flow as measured using xenon,
way, is increased in human subjects with Alzheimer’s disease
on autopsy (88). If hyperglycemia from diabetes shunts glu- and the magnitude of reduction correlates with the duration
cose toward the production of chitin, it is possible that the of the disease. However, blood glucose levels were not con-
accumulation of this molecule could contribute to abnormal- trolled during the experiment (range, 3.1–21.2; mean, 8.8 ⫾
ities in cognition. 4.74 mmol/liter) (97). Interestingly, the rate of cerebral blood
Hyperglycemia has also been proposed to cause end organ flow in patients with diabetes is similar to that found in
damage through increases in reactive oxygen species, in par- Alzheimer’s patients with dementia (92). These observations
ticular superoxide, which could then lead to increased polyol in humans with diabetes are supported by studies in strep-
pathway activation, increased formation of AGEs, activation tozotocin-treated rats with chronic hyperglycemia (mean
of protein kinase C, and increased glucose shunting in the plasma glucose, approximately 29 mmol/liter) (98). One can
hexosamine pathway (76). Using streptozotocin to induce speculate that the decrease in cerebral blood flow, coupled
diabetes in rats (blood glucose, 20.72 ⫾ 2.25 vs. 6.04 ⫾ 0.64 with the stimulation of the thromboxane A2 receptor known
mmol/liter in control rats), Aragno et al. (89) found that to occur in patients with diabetes (92), could contribute to the
RAGEs, galectin-3 (a proatherogenic molecule), and the inability of cerebral vessels to adequately vasodilate, which
polyol pathway activation all were increased in rat brains, may in turn increase the likelihood of ischemia. The coex-
whereas activity of the glycolytic enzyme glyceradehyde-3- istence of ischemia and hyperglycemia may be particularly
phosphate dehydrogenase was decreased, indicating ele- detrimental to the brain. Even modestly elevated blood glu-
vated superoxide levels. Nuclear factor ␬B transcription fac- cose levels (greater than 8.6 mmol/liter) in humans during
tors, a proinflammatory gene marker up-regulated by AGEs, a cerebrovascular event correlates with poorer clinical re-
and S-100 protein, a marker for brain injury that can bind to covery (99). One potential mechanism through which hy-
RAGEs, were both up-regulated in the hippocampus in this perglycemia could potentiate ischemic damage is lactate ac-
animal model, although the effect in other regions was not cumulation. Hyperglycemia provides more substrate for
assessed. These data suggest that oxidative stress may trigger
lactate to form, causing cellular acidosis and worsening in-
a cascade of events that lead to neuronal damage. Interest-
jury (93). Another mechanism is the accumulation of gluta-
ingly, dehydroepiandrosterone, an adrenal androgen and
mate in the setting of hyperglycemia and ischemia (100).
antioxidant, significantly reduces these changes, suggesting
a potential therapy worthy of more investigation. Glutamate, an excitatory amino acid neurotransmitter, has
In addition to hyperglycemic-induced end organ damage, been shown to cause neuronal damage in the brain (101).
altered neurotransmitter function has been observed in di- Although the exact mechanism is not known, the lack of
abetic models and may also contribute to cognitive dysfunc- C-peptide in patients with type 1 diabetes may by itself
tion. In diabetic rats (blood glucose 28.6 ⫾ 1.1 vs. 6.3 ⫾ 0.2 worsen cognitive impairment through its actions on the en-
mmol/liter in control rats), there is an impairment of long- dothelium. Evidence for this is suggested by a rat model
term potentiation, defined as activity-dependent prolonged (blood glucose approximately 23 mmol/liter) in which re-
enhancement of synaptic strength, in neurons rich in recep- placement of C-peptide to normal levels normalized cogni-
tors for the neurotransmitter N-methyl-d-aspartate (NMDA), tive function and reduced hippocampal apoptosis (102). The
which could contribute to learning deficits (90). Other, neuro- relevance to humans is uncertain, however, because humans
chemical changes have been observed, including decreased with type 1 diabetes do not have hippocampal atrophy (103).
C. The role of hypoglycemia found to be widely distributed in rat brain using immuno-
histochemistry and in situ hybridization (114, 115), respec-
As mentioned in Section II.C, whether repeated episodes of
tively, including in the olfactory bulb, hypothalamus, hip-
hypoglycemia contribute to cognitive dysfunction is contro-
pocampus, cerebellum, piriform cortex, cerebral cortex, and
versial and most likely depends on the age of the patient.
amygdala. The insulin-responsive glucose transporter 4
However, there is no argument that if severe hypoglycemia
(GLUT4) has also been found in select regions of the rat brain,
lasts for a very long time, brain damage and death can occur
including the pituitary, hypothalamus, and medulla (116).
(93, 104 –106). Most endocrinologists have personal experi-
GLUT8, also known as GLUTx1, is also found in the rat brain,
ence with patients who have experienced severe hypogly-
specifically in the hippocampus, hypothalamus, cerebellum,
cemia (⬍2 mm) with little or no permanent consequence. This
and brainstem (117). GLUT8 has similar properties to GLUT4
most likely is secondary to inaccuracies of glucometer at low
and is up-regulated in response to insulin in some (118) but
blood glucose levels (107), inadequate time with severe hy-
not all murine tissues, including the brain (119). Despite the
poglycemia, or variations in patients’ glycogen stores. That
presence of insulin receptors and insulin-sensitive glucose
said, it has been shown in animal models that after 30 – 60 min
transporters, the effect of insulin on cerebral glucose metab-
of blood glucose levels between 0.12 and 1.36 mmol/liter,
olism is still uncertain. Many laboratories, including our
neuronal necrosis occurs with accompanying extracellular
own, have failed to demonstrate an effect of insulin on ce-
increases in aspartate, alkalemia, and neuronal energy fail-
rebral glucose metabolism in humans (120 –122). However,
ure, ultimately leading to a flat electroencephalograph (EEG)
other laboratories using fluorodeoxyglucose positron emis-
(105, 106). The cortex, basal ganglia, and hippocampus ap-
sion tomography (PET) have found a significant increase in
pear to be most vulnerable to hypoglycemia, with laminar
brain glucose metabolism in the setting of hyperinsulinemia
necrosis and gliosis found in these regions on autopsies per-
in humans (123), an effect that is reduced in subjects with
formed in human patients who died of hypoglycemia (104).
peripheral insulin resistance (124). Despite the ongoing con-
Other human autopsy studies done after death secondary to
troversy of the effect of insulin on cerebral glucose metab-
hypoglycemia have shown multifocal or diffuse necrosis of
olism, there is a large and growing body of evidence that
the cerebral cortex and chromatolysis of ganglion cells (108).
insulin resistance, long recognized as a factor contributing to
In animal models, hypoglycemia-induced damage seems to
the onset of type 2 diabetes, may play a role in the patho-
be selective to neurons with sparing of astrocytes and oli-
genesis of Alzheimer’s disease.
godendrocytes (92). Although counterintuitive, the time to
The clinical diagnosis of Alzheimer’s disease is made in the
neuronal death may be asymmetric between hemispheres in
presence of a significant gradual and progressive decline in
severe, prolonged hypoglycemia, making the differentiation
memory with at least one other cognitive, social, or occupa-
of hypoglycemic brain damage from ischemia difficult on a
tional disturbance (125). The incidence of Alzheimer’s dis-
clinical basis (105). Some have hypothesized that hypogly-
ease has been found to be approximately 1.2- to 1.7-fold
cemia-induced neuronal damage occurs as a result of over-
higher in patients with type 2 diabetes and insulin resistance
activation of a subtype of the excitatory neurotransmitter
compared with a control population in most (37– 43, 47), but
NMDA receptor (109). Interestingly, there exists an NMDA
not all (126 –128), investigations. The reason for the discrep-
receptor antagonist that has been shown to prevent neuronal
ancy could be the populations studied. Data that support a
necrosis, suggesting a potential therapy for hypoglycemia-
relationship between Alzheimer’s and insulin resistance all
induced brain damage (110). Such a therapy may be helpful
examined older subjects ascertained from the general pop-
in young children with type 1 diabetes who seem to be
ulation. The reports that failed to find an association collected
particularly susceptible to cerebral complications of hypo-
data from a more narrowly defined population, such as
glycemia. There may also be a relationship to hypoglycemia
those with a high incidence of the apolipoprotein E type 4
during early nocturnal sleep, a time in which consolidation
(APOE-␧4) allele (128) or a high percentage of early-onset
of memories occurs, and cognitive dysfunction. Compared
Alzheimer’s disease (126). Interestingly, it appears that
with test outcomes after a night of sleep in euglycemia,
type 2 diabetes is also more common in populations with
human control subjects and subjects with type 1 diabetes
Alzheimer’s disease (129). Whether the association between
exhibited impaired declarative memory (memory of facts)
Alzheimer’s disease and patients with type 2 diabetes reflects
after undergoing a short, relatively mild hypoglycemic
the impact of poor metabolic control on brain function or the
clamp (2.2 mmol/liter) during early sleep (111). However, no
actual effects of insulin and insulin resistance on the brain is
neurocognitive deficits were seen in several other studies in
unclear. Patients with Alzheimer’s disease and normal glu-
which nocturnal hypoglycemia was induced later during the
cose tolerance have a more robust insulin secretory response
sleeping period (112, 113).
to an oral glucose load than controls, suggesting that they
may have increased insulin resistance (130, 131). Some have
D. The role of insulin resistance and amyloid suggested that the insulin resistance occurs in the brain itself
and have hypothesized that the desensitization of neuronal
Although the role of insulin on cerebral metabolism and insulin receptors plays an important role in the development
function is still evolving, fascinating research has given us of sporadic Alzheimer’s disease (132). Such a concept is sup-
more insight into this field over the last 20 yr. Historically, ported by observations that patients with Alzheimer’s dis-
the brain was thought to be an insulin-independent organ; ease have an elevated concentration of insulin in their cere-
however, many recent discoveries have questioned that no- bral spinal fluid under fasting conditions (131), along with an
tion. Insulin receptors and mRNA expression have been increase in insulin receptor density in the occipital region and
a decrease in tyrosine kinase activity (which is downstream ment for 8 wk improved delayed recall, enhanced mood, and
to insulin binding) in the temporal and occipital lobes com- self confidence and reduced anger in nondiabetic, nonde-
pared with controls (133). However, others have found that mentia subjects (151). Based on these studies, it is hypothe-
patients with Alzheimer’s disease have a decrease in cerebral sized that in Alzheimer’s disease, cerebral insulin resis-
spinal fluid insulin levels, suggesting that there may be im- tance requires higher levels of insulin to facilitate memory
paired insulin transport across the blood brain barrier or (46, 152). Although cerebral insulin is higher in these pa-
increased insulin catabolism that accounts for the impaired tients, it may not be enough to compensate for the insulin
central insulin action (134). resistance. However, this does not necessarily prove that
The mechanisms through which insulin resistance might hyperinsulinemia directly improves cognitive function. Hy-
alter cognitive function remain uncertain, but effects on neu- perinsulinemia can stimulate epinephrine release, and both
rotransmission and memory formation have been hypothe- insulin and epinephrine have been shown to increase lactate
sized. An impairment in central cholinergic activity is be- (153). Lactate can then in turn be used as a source of energy
lieved to contribute to the pathogenesis of Alzheimer’s in brain metabolism (154, 155), although the benefits of lac-
disease (135), and interestingly, rats with streptozotocin- tate therapy have not been proven to be beneficial yet in
induced diabetes have a decrease in the production and Alzheimer’s patients (156).
release of acetylcholine compared with control rats (91). Mice Insulin resistance and type 2 diabetes mellitus may con-
models in which cholinergic activity is blocked by scopol- tribute to cognitive dysfunction through three other indirect
amine experience amnesia and hyperactivity, a deficit that mechanisms. First, cognitive dysfunction in patients with
can be reversed by glucose administration (136, 137). Glucose type 2 diabetes has been correlated to inflammatory markers,
administration with a rise in endogenous insulin levels or and increased inflammation may contribute to the develop-
insulin administration to patients with Alzheimer’s disease ment of Alzheimer’s or macrovascular disease. In one in-
have also been shown to alter behavior, perhaps by enhanc- vestigation, patients with the metabolic syndrome, elevated
ing cholinergic activity (138). In these studies, patients with C-reactive protein, and elevated IL-6 were found to have
Alzheimer’s demonstrated an improvement in declarative impaired cognitive function, whereas those patients with
memory during either a hyperglycemic or a hyperinsuline- the metabolic syndrome and normal levels of these inflam-
mic euglycemic clamp (138, 139). Furthermore, patients with
matory markers had similar cognition to controls (47). Pa-
memory impairment and Alzheimer’s disease had improved
tients with type 2 diabetes are known to have higher levels
verbal memory acutely after intranasal insulin administra-
of inflammatory markers including C-reactive protein, ␣-
tion, which had no effect on peripheral glucose or insulin
1-antichymotrypsin, IL-6, and intercellular adhesion mole-
levels but had previously been shown to increase central
cule 1 than control populations (157). These findings raise the
nervous system insulin levels (140). In addition to affecting
possibility that insulin resistance and Alzheimer’s disease
cholinergic activity, diabetes and insulin may affect long-
share a common pathophysiology, because patients with
term potentiation in opposing ways. Long-term potentiation
Alzheimer’s disease demonstrate increased inflammatory
is critical to the formation of memories and is induced by
NMDA receptor activation, a process that is up-regulated in markers as well (158, 159).
the presence of insulin (141). However, rats with diabetes, A second potential mechanism through which insulin re-
and presumed relative insulin deficiency, have decreased sistance and type 2 diabetes could contribute to cognitive
long-term potentiations in the hippocampus as measured by dysfunction is through the disruption of the hypothalamic-
electrophysiology (90). As would be expected if long-term pituitary adrenal axis. Both animals (160) and humans (161)
potentiation were reduced, rat hippocampal neurons ex- with type 2 diabetes have an up-regulation of the hypotha-
posed to insulin exhibited inhibition of spontaneous firing lamic-pituitary-adrenal axis, with increased serum cortisol
(142). Interestingly, patients with Alzheimer’s disease have compared with controls. In other research, hypercortisolemia
a reduced cerebral glucose uptake as measured by PET has been found to cause cognitive dysfunction. Healthy hu-
(143–145) and have a reduced number of glucose transport- mans treated with dexamethasone (162), corticosterone (163),
ers in the brain microvessels, frontal cortex, hippocampus, and hydrocortisone (164) to mimic stress conditions all per-
caudate nucleus, parietal, occipital, and temporal lobe com- formed worse on memory testing. In a study of healthy
pared with controls on autopsy studies (146, 147). Perhaps elderly patients, those with higher serum cortisol levels per-
the reduction in glucose uptake has a direct effect on how formed more poorly on memory and attention testing (165).
insulin regulates hippocampal function in these patients. In addition, patients with Cushing’s disease have been found
Future experiments to identify the relative roles of glucose to have worse performance on memory, attention, reasoning,
and insulin in human cognition are necessary to clarify these and concept formation testing compared with controls (166),
relationships. which may be attributed to a significant reduction in cerebral
The impact of insulin on cognitive function has also been glucose metabolism found on PET scan in those patients with
examined in control subjects without Alzheimer’s disease or Cushing’s disease (167). Supporting these findings are the
diabetes mellitus. In our laboratory, we found that inducing animal studies in which glucocorticoids cause structural
hyperinsulinemia using an insulin infusion in control sub- damage and reduce function of neurons in the hippocampus
jects reduces parietal region P300 amplitude secondary to (168 –172). Based on the facts that type 2 diabetes causes an
memory triggers (148). Other clamp studies found improved up-regulation of the hypothalamic-pituitary-adrenal axis
vigilance, memory, and selective attention in the setting of and hypercortisolemia can cause cognitive dysfunction, it
hyperinsulinemia (149, 150), whereas intranasal insulin treat- can be hypothesized that the increase in cortisol levels seen
in patients with type 2 diabetes may contribute to cognitive shared pathogenesis may be present in patients with type 2
dysfunction. diabetes and patients with Alzheimer’s disease, possibly in-
The third potential mechanism through which insulin re- volving a defect in a chaperone protein (191) that helps
sistance may indirectly contribute to cognitive dysfunction intracellular protein trafficking (129). Rat models of type 2
is by promoting the formation of senile plaques found in diabetes (BBZDR/Wor), even more so than type 1 (BB/Wor)
Alzheimer’s disease. Intracellular neurofibrillary tangles and diabetes, demonstrate an increase in Alzheimer’s pathology,
extracellular senile plaques composed of ␤-amyloid are the including increased APP, ␤-amyloid, and ␤-secretase and
pathological hallmarks of Alzheimer’s disease (173–175). loss of neurons (192). Despite this compelling evidence link-
␤-Amyloid is formed from the cleavage of amyloid precursor ing insulin resistance and type 2 diabetes mellitus to Alz-
protein (APP), produced in neurons (176), by the enzymes heimer’s disease and pathology, several autopsy studies per-
␤- and ␥-secretase (177). ␤-Amyloid is eventually degraded formed in humans have failed to identify an increase in senile
by the insulin-degrading enzyme (178, 179). Amyloid ␤- plaques or neurofibrillary tangles in subjects with diabetes
peptides can by themselves bind to RAGEs and bring about compared with age-matched controls (83, 129), although the
microglial and neuronal dysfunction and oxidative stress duration of diabetes did correlate with the density of senile
(81). Interestingly, amyloid ␤-peptides, AGEs, and RAGEs plaques in one of these studies (129).
have all been colocalized in astrocytes using immunohisto- The relationship between insulin resistance and cognitive
chemistry in human brain slices (180). In addition, there is a dysfunction in Alzheimer’s disease appears to depend on the
growing body of evidence that insulin and insulin resistance presence or absence of the APOE-␧4 allele. Curiously, al-
can affect the metabolism of APP and ␤-amyloid, thus po- though the presence of the APOE-␧4 allele is associated with
tentially increasing the burden of cerebral senile plaques. The an increased incidence of Alzheimer’s disease (193), it seems
role of insulin resistance in the metabolism of APP and that insulin resistance is only a significant risk factor for
␤-amyloid was further clarified by Craft et al. (181). In their Alzheimer’s disease in those patients without the APOE-␧4
experiment, plasma levels of APP, the precursor to ␤-amy- allele (39, 134). Patients with Alzheimer’s disease and no
loid, were lower in those subjects with insulin resistance and APOE-␧4 allele have been observed to have lower glucose
Alzheimer’s disease when undergoing a hyperinsulinemic- disposal rates during a hyperinsulinemic-euglycemic clamp
euglycemic clamp. This corresponded with improved mem- than subjects with Alzheimer’s disease and the APOE-␧4
ory testing. One potential explanation of this observation is allele, as well as those subjects without Alzheimer’s disease
that insulin resistance may cause decreased APP degradation or the APOE-␧4 allele. Subjects with Alzheimer’s disease
that can be overcome by the elevating serum and presumably without the APOE-␧4 allele also had improved memory
tissue insulin levels (181). Similar findings have come from scores in the setting of hyperinsulinemia, which was not the
experiments in rat hippocampal neurons, where insulin was case in APOE-␧4 allele-positive subjects (149, 181). Based on
found to up-regulate insulin degrading enzyme, thereby in- this information, it seems that insulin resistance/type 2 di-
creasing ␤-amyloid degradation (182). However, not all stud- abetes and APOE-␧4 allele positivity are distinct and separate
ies have agreed with this hypothesis. In a study using neu- risk factors for the development of Alzheimer’s disease, a
roblastoma cell lines by Gasparini et al. (178), insulin was hypothesis that is supported by the fact that those with
found to decrease intracellular ␤-amyloid and increase ex- diabetes had a low incidence of the APOE-␧4 allele (128).
tracellular levels of ␤-amyloid by both promoting its secre- However, there is again a contradiction in the literature; in
tion and inhibiting its degradation via the insulin-degrading the Honolulu-Asia Aging Study, those subjects with both
enzyme. This would contradict the majority of the evidence type 2 diabetes and the APOE-␧4 allele had an additive
that insulin has a protective effect against memory loss. increased risk of dementia and Alzheimer’s pathology (43).
However, whereas it is widely believed that extracellular This study was specific for elderly Japanese-American men,
accumulation of ␤-amyloid plays a critical role in the devel- so it seems that additional multiethnic studies are needed to
opment of Alzheimer’s, other evidence is suggesting there is understand this discrepancy better.
a pathogenic role for intracellular ␤-amyloid (183–185). More The association between insulin resistance and Alzheimer’s
research is needed concerning the pathophysiology of disease has been sufficiently compelling for investigators
␤-amyloid and insulin before conclusions can be drawn. to examine whether peroxisome proliferator-activated
Of interest is the observation that the pancreatic islets in receptor-␥ (PPAR-␥) agonists can treat Alzheimer’s disease
patients with type 2 diabetes mellitus are characterized by in the absence of diabetes. To date, two trials have demon-
␤-cell loss and deposition of islet amyloid (186), which is strated rosiglitazone to have a beneficial effect on memory in
reminiscent of the neuronal loss and ␤-amyloid deposition patients with Alzheimer’s disease. In a small randomized
seen in Alzheimer’s disease (187). The constitutions of islet study published by Watson et al. (194) in 2005, patients with
and neural ␤-amyloid are similar (129, 188), and both are mild Alzheimer’s disease treated for 6 months with rosigli-
toxic to islet and neurons, respectively (189, 190). In a series tazone had better memory and selective attention than con-
of 29 patients in whom both brain and pancreas autopsy trols. A much larger study published in 2006 found that
specimens were available, all had amyloid detected to some patients with Alzheimer’s disease without the APOE-␧4 al-
degree in both the brain and pancreas (187). In another study, lele had improvements in cognitive testing after 6 months of
islet amyloid was more abundantly present on autopsy in rosiglitazone, whereas those Alzheimer’s disease patients
patients with Alzheimer’s disease than in those without with the APOE-␧4 allele did not have improvements (195).
Alzheimer’s disease (129). Based on the similarity between Multiple mechanisms have been proposed to address how
islet and neural ␤-amyloid, some have speculated that a PPAR-␥ agonists may affect the pathophysiology responsible
for Alzheimer’s disease, including reducing serum glucocorti- TABLE 3. Summary of modalities for assessment of cognitive
coids (196), decreasing glial inflammation (197, 198), protecting dysfunction in patients with diabetes
against ␤-amyloid-induced neurodegeneration (199), decreas-
Neurocognitive testing
ing ␤-amyloid production (197), increasing ␤-amyloid degra- Evoked response potentials
dation (196, 200), and decreasing phosphorylation of tau pro- EEG
teins, the mechanism by which neurofibrillary tangles are MRI
formed (201). Interestingly, despite all of these data, it is still fMRI
SPECT
not totally clear how rosiglitazone benefited patients with PET
Alzheimer’s disease in clinical trials because it has been shown
not to cross the blood-brain barrier (196). These data are com-
pelling enough to warrant further, longer-term studies on the tentials can reveal subclinical sensory nerve conduction def-
benefits of PPAR-␥ agonists in the treatment of Alzheimer’s icits that may not otherwise be apparent (206). For example,
disease. However, clinicians must weight the benefits against flash electroretinography has shown decreased potentials
the newly documented cardiovascular risks of these treatments from the retina in diabetic subjects before ophthalmoscopic
(202, 203). signs of retinopathy were seen (108). In addition, pattern
electroretinogram, which looks at the pattern of retinal stim-
uli originating from the ganglion cells, is also decreased in
IV. Modalities for Assessment of Cognitive patients with diabetes (108). The evoked response of nerves
Dysfunction in Patients with Diabetes involved in sensing auditory stimuli is also abnormal; brain-
stem auditory-evoked potentials demonstrated acoustic
Although progress is being made, the difficulty of detect- pathway impairment in patients with diabetes (207–209).
ing neurocognitive dysfunction in patients with diabetes in Evoked potentials related to memory may also be affected
the clinical setting may explain in part why the field of because auditory P300 event-related potentials had signifi-
cognitive dysfunction in diabetes has not advanced similarly cantly longer latencies in patients with type 2 diabetes com-
to other fields dealing with hyperglycemia-associated end pared with controls, which could relate to attention and
organ damage. Neurocognitive testing in which an examiner short-term memory defects (210). Central somatosensory-
administers a battery of tests to assess different aspects of evoked potentials were found to be prolonged in patients
cerebral function has long been the gold standard for the with diabetes as well (211). In another study looking at both
assessment of neurocognitive function. Although cumber- type 1 and type 2 diabetes, slowed latency in visual and
some to administer and score, it has been very useful in somatosensory-evoked potentials was observed in patients
assessing neurocognition in a variety of disease states, in- with type 1 diabetes, whereas patients with type 2 diabetes
cluding diabetes, as was demonstrated in Section II. How- had slowed latency of visual, somatosensory, and brainstem
ever, such tests have a relatively high rate of intrasubject auditory-evoked potentials (212). In this investigation, in-
variability that reduces their ability to identify mild deficits creasing HbA1c was related to reduced cognitive perfor-
or preclinical disease. Also, many studies examining the mance. Event-related potentials have also helped define
effect of diabetes on brain function use multiple neurocog- brain adaptations to hypoglycemia. During hypoglycemia,
nitive tests that assess the same psychological process. When normal subjects do not experience a delay in initial percep-
the results of these different tests don’t agree, determining tion and precognitive processing, but they do have a delay
which results to base conclusions on can be confusing (204). in central processes such as stimulus selection and selective
In addition, not all neurocognitive tests are created equal. central motor activation (213). Of note, although all except
Although many neurocognitive tests are well validated in a one of these studies controlled for hypoglycemia during
diverse population to distinguish between “normal” and testing (211), none of the studies adequately controlled for
“abnormal” results, other tests do not have adequate reli- hyperglycemia during testing, although Kurita et al. (210)
ability data, are based on unacceptably small norms, are found no difference between those subjects with high and
administered inappropriately, or do not properly distinguish relatively normal blood glucose values.
between two or more diagnostic groups (205). Finally, neu- EEG can also assess spontaneous cerebral electrical activ-
rocognitive testing is unable to provide specific information ity and has been used in patients with type 1 and type 2
about the neural structures responsible for any dysfunction diabetes. Patients with type 2 diabetes have been found to
identified. For example, although it appears that white mat- have slowing in the EEG frequency band analysis over the
ter function such as processing speed, attention, and visual- central cortex area and reduction of alpha activity over the
spatial processing are particularly affected by diabetes (4), parietal area. These findings correlated with reduced visual
localization of this dysfunction to white or gray matter is not retention on neurocognitive testing but were not simply re-
possible using the battery of tests available to assess lated to hyperglycemia because making nondiabetic subjects
neurocognition. with hyperglycemia did not reproduce these findings (32).
Because of the limitations in neurocognitive testing, a Subjects with type 1 diabetes have also been found to have
number of modalities have been used to assess cognitive abnormal EEG results compared with controls, with those
function in patients with diabetes (Table 3). One of the oldest patients with a history of having severe hypoglycemia hav-
modalities has been to measure electrical activity such as ing the most abnormalities (65, 214, 215).
evoked response potentials in the brain after the adminis- Magnetic resonance imaging (MRI) has been used in a
tration of different stimuli. Abnormal evoked response po- number of studies to examine cerebral structure in patients
with type 1 and type 2 diabetes and has pretty consistently (221). Wessels et al. (222) performed a similar experiment but
found the brains of such subjects to have leukoariosis, which compared patients with type 1 diabetes and retinopathy,
are hyperintense white matter lesions (207, 216). One study patients with type 1 diabetes and no retinopathy, and con-
found that 69% of middle-aged adults with long-standing trols. They found that patients with type 1 diabetes and
type 1 diabetes had abnormal MRI scans, compared with 12% proliferative retinopathy had decreased gray matter density
of healthy, aged-matched volunteers, with an increased in the right inferior gyrus and right occipital lobe compared
number of larger, high-signal lesions in the cerebrum, cer- with those patients with diabetes and no retinopathy, as well
ebellum, and brain stem being the primary abnormality iden- as to controls. More recently, Wessels and colleagues applied
tified (207). However, this was not confirmed by a more voxel-based morphometry to white matter volumes. They
recent published study in which relatively young patients found that those subjects with type 1 diabetes and prolifer-
(25– 40 yr old) with type 1 diabetes for more than 15 yr did ative retinopathy had significantly smaller white matter vol-
not have a significant difference in white matter hyperin- ume than subjects without diabetes, and that smaller white
tensities compared with healthy controls. In addition, white matter volume correlated with worse performances on at-
matter hyperintensities did not correlate with depressive tention, speed of information processing, and executive func-
history, retinopathy, severe hypoglycemia, glycemia control, tion. This was not seen in patients with type 1 diabetes who
and most neurocognitive tests (with the exception of delayed had no proliferative retinopathy, suggesting a possible com-
memory) (7). This is in agreement with previous studies mon mechanism in the development of retinopathy and ce-
(3, 217). The reason for the discrepancy may have been that rebral dysfunction (6). Preliminary findings by Perantie et al.
subjects in the former study had more severe microvascular (223) have found that a history of severe hypoglycemia in
complications and that differences in cardiovascular risk fac- children is associated with decreased gray matter in the left
tors between subjects with diabetes and controls were not superior temporal region, whereas increased HbAlc levels
controlled for. In patients with type 2 diabetes, these white are associated with reductions of gray matter in the right
matter hyperintensities have been noted to correlate with cuneus and precuneus regions, reductions of white matter in
reduced performance on tests of attention, executive func- the right posterior parietal region, and increased gray matter
tion, information processing speed, and memory (216, 218). in the right prefrontal cortex.
The nature of these white matter lesions is uncertain, but Functional MRI (fMRI) has also been used to assess cere-
investigators have hypothesized that they could represent bral function in patients with diabetes. fMRI is based on the
demyelination, increased water content, angionecrosis, cys- fact that increases in cerebral blood flow and metabolism
tic infarcts, or gliosis (i.e. brain tissue scarring) (92). during stimulus-induced neuronal activation are accompa-
MRI has also demonstrated that subjects with type 2 di- nied by a relative reduction in deoxyhemoglobin content of
abetes have hippocampal and amygdala atrophy relative to the activated tissue relative to the adjacent unactivated brain.
control subjects (219). The hippocampus and amygdala are Because deoxyhemoglobin is a paramagnetic molecule, it can
responsible for such functions as memory and behavior and, be visualized by MRI. Rosenthal et al. (224) applied fMRI to
interestingly, are also found to be atrophied in Alzheimer’s the study of cerebral function during standard neurocogni-
patients (219). However, a similar study in subjects with type tive testing in subjects with type 1 diabetes subjected to both
1 diabetes failed to identify reductions in hippocampal and euglycemia and hypoglycemia. They found that the effect of
amygdala volume, although these subjects did have an in- acute hypoglycemia on cerebral blood flow is task and region
crease in cerebrospinal fluid on MRI, suggesting mild global specific. For example, during hypoglycemia, the slower fin-
cerebral atrophy (103). Another study compared MRI find- ger tapping corresponded to decreased activation of the right
ings and neuropsychometric testing in patients with an early premotor cortex, supplementary motor area, and left hip-
age of onset of type 1 diabetes (younger than age 7) and a later pocampus and with increased activation in the left cerebel-
age of onset (7–17 yr old). Subjects with early onset disease lum and right frontal pole. In addition, during hypoglycemia
had larger ventricular volumes and more prevalent ventric- deterioration of four-choice reaction time correlated with
ular atrophy than those with later onset, which corresponded reduced activation in the motor and visual systems but with
to poorer intellectual and information processing ability (220). increased activation of the part of the parietal cortex involved
Atrophy in subcortical and periventricular areas has also been in planning (224). More recently, Wessels et al. (24) applied
associated with reduced performance on memory tasks in pa- this methodology to determine whether subjects with type 1
tients with type 2 diabetes (216). A history of hypoglycemia diabetes with known hyperglycemia-induced end organ
appears to be related to an increase in cerebral atrophy (70). damage, specifically retinopathy, had differing areas of ce-
Recently, voxel-based morphometry, in which differences rebral activation with cognitive stimuli and hypoglycemia
in local characteristics of tissue are measured using MRI, has compared with patients with type 1 diabetes and no micro-
been used to evaluate both the gray and white matter of vascular complications. Although there was no difference
patients with type 1 diabetes. Musen et al. (221) found that seen in cognitive ability between the two groups, there was
compared with controls, patients with type 1 diabetes had an overall increase in activation and less appropriate deac-
lower gray matter density in certain areas of the temporal tivation of certain brain regions during hypoglycemia in the
lobe, frontal lobe, and thalamus. They also found that higher diabetic group with retinopathy. The investigators hypoth-
HbA1c levels correlated with lower gray matter density in esized that regional alterations in activation were secondary
areas important for language, memory, and attention, to hyperglycemia-induced end organ damage in the central
whereas a history of severe hypoglycemia correlated with nervous system, causing altered neurovascular coupling or
less gray matter density in the left cerebellar posterior lobe functional microvascular alterations (24). Preliminary find-
ings by Musen et al. (225) have found decreased activation in cursor to true dementia or represent another process. We also
the superior temporal gyrus and the parahippocampal gyrus do not know whether the incidence of dementia is increased
in response to lexical and recognition stimuli, respectively, in in patients with type 1 diabetes compared with the rest of the
a group composed of patients with long-standing type 1 population. In prior decades, this was not an issue because
diabetes compared with controls. patients with type 1 diabetes died at relatively young ages
Other imaging modalities such as single photon emission from other complications of the disease. However, now that
computed tomography (SPECT) and PET have been used to patients with type 1 diabetes are living longer and better with
assess cerebral function in patients with diabetes mellitus. the disease, this must be assessed. Finally, it is not clear
SPECT is particularly good at assessing cerebral perfusion whether the subtle cognitive deficits identified in many stud-
and has demonstrated in an uncontrolled study that patients ies truly impact the lives of patients living with diabetes (34).
with type 2 diabetes and dementia have a high incidence of Future studies, perhaps longitudinal in nature or involving
hypoperfusion in at least one area of the brain (226). How- better serum/imaging biomarkers, will be of tremendous
ever, SPECT has also demonstrated that patients with type benefit in providing better understanding of the natural his-
1 diabetes have hyperperfusion in the prefrontal and frontal tory of this complication.
brain regions compared with controls (227). Other investi- Future study will also be important in understanding the
gators found that when the SPECT data are corrected for the pathogenesis of cognitive dysfunction secondary to diabetes.
increase in cerebral atrophy seen in patients with diabetes, Although it seems that hyperglycemia and hyperglycemia-
cerebral blood flow and glucose metabolism values were induced end organ damage contribute to this problem, the
within normal range (228). PET with fluorodeoxyglucose is actual mechanisms through which hyperglycemia alters ce-
a technique that can be used to assess glucose metabolism rebral structure and function are not clear. Improved glyce-
because the compound is taken up and trapped in the cell by mic control is likely of therapeutic benefit, as has been sug-
phosphorylation. When this method was used in patients gested by many retrospective studies (5, 15–18, 26 –28, 48),
with type 1 diabetes and a history of severe hypoglycemia but a prospective study is needed to determine whether this
and hypoglycemia unawareness, no differences in glucose is true. In addition, identification of the mechanisms through
metabolism were found relative to controls, although neu- which hyperglycemia may impair cognitive function in pa-
ropsychological testing was also not significantly different tients with diabetes will stimulate new research into ways to
(69). Two pilot studies, one by our own laboratory, have prevent and treat all of the hyperglycemia-associated com-
used diffusion tensor imaging, a type of MRI that mea- plications of diabetes.
sures white matter integrity quantitatively by fractional
anisotropy (229, 230), in patients with diabetes. Prelimi-
nary findings show a reduction in white matter integrity VI. Conclusion
in patients with type 1 diabetes that was associated with In conclusion, there have been significant gains in our
severity of hyperglycemia (231) and poorer performance understanding of the effect of diabetes on cognitive dys-
on certain neurocognitive tests (67). function. Evidence from neurocognitive testing suggests that
In general, assessment modalities to detect cognitive dys- cognitive dysfunction should be listed as one of the many
function associated with diabetes have been disappointing. complications of diabetes, along with retinopathy, neurop-
Neurocognitive testing is cumbersome and lacks pathophys- athy, nephropathy, and cardiovascular disease. The patho-
iological insight. Evoked response potentials and EEG seem genesis of cognitive dysfunction is only partially understood.
to be good at detecting sensory/perception deficits but are Although many studies suggest that changes in cerebral
also cumbersome and do not provide as much information structure and function in diabetes are related to hypergly-
about more complex cognitive functions. Although promis- cemia-induced end organ damage, macrovascular disease,
ing, there have been conflicting results with regard to MRI hypoglycemia, insulin resistance, and amyloid lesions may
studies, specifically in patients with type 1 diabetes. The play a role in some patients. Greater understanding of the
utility of SPECT, PET, and diffusion tensor imaging in mon- natural history of this diabetes complication and the mech-
itoring or detecting changes in patients with cognitive dys- anisms responsible for its development will continue to ad-
function and diabetes remains to be determined. vance as biochemical and imaging modalities continue to
evolve. As new knowledge is gained, it can be applied to
develop new and improved ways to prevent and treat all of
V. Future Directions the hyperglycemia-related complications of diabetes.
Although much research has been done on the impact of
diabetes mellitus on cognitive function, many questions still Acknowledgments
remain. It is clear that patients with type 1 and type 2 diabetes
have been found to have abnormalities in neurocognitive Received October 1, 2007. Accepted March 28, 2008.
function, although the natural history and clinical signifi- Address all correspondence and requests for reprints to: Elizabeth R.
cance of these findings have not yet been clearly defined. For Seaquist, M. D., Department of Medicine, Division of Endocrinology and
example, we know that there is an increased incidence of Diabetes, University of Minnesota, Campus Delivery Code 1932, Suite
229, 717 Delaware Street SE, Minneapolis, Minnesota 55414. E-mail:
dementia in patients with type 2 diabetes (37, 38, 40 – 44), but seaqu001@umn.edu
we do not know whether the more subtle changes in memory This work was supported by NIH Grants NS35192 (to E.R.S.),
and in other measures on neurocognitive testing are a pre- DK62440 (to E.R.S.), and 2 T32 DK007203–29A1 (to C.T.K.).
Disclosure Statement: E.R.S. has served on advisory boards for Pfizer alters mood state and impairs cognitive performance in people with
and Merck. C.T.K. has no disclosures to state. type 2 diabetes. Diabetes Care 27:2335–2340
22. Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP
2005 The effects of type 1 diabetes on cognitive performance: a
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00/0 Endocrine Reviews 29(4):494 –511

Cognitive Dysfunction and Diabetes Mellitus

I. Introduction nitive dysfunction, and many patients fear that recurrent

First Published Online April 24, 2008

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